Open-label Phase 2 of tabelecleucel in Subjects with Epstein Barr Virus associated Diseases (EBVision)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pierre Fabre Medicament

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

17 Mar 2021 → ongoing

Decision date (initial)

2024-10-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Pierre Fabre Medicament

External identifiers

EU CT number

2024-516623-14-00

EudraCT number

2020-000177-25

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To determine the clinical benefit of tabelecleucel in participants with EpsteinBarr virus (EBV) associated diseases as measured by the objective response rate (ORR)

Secondary objectives 1

1. To evaluate additional clinically relevant outcomes in EBV-associated diseases treated with tabelecleucel

Conditions and MedDRA coding

EBV+ primary imunodeficiency lymphoproliferative disease (LPD)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002025-PIP04-19

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1.ECOG performance status ≤3 for participants aged ≥16 years; Lansky score ≥20 for participants from ≥1 year to <16 years
2. 8. Participants may have systemic and CNS disease, or CNS disease only meeting the following criteria: a.When present, systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18F-deoxyglucose avidity, except when contraindicated or mandated by local practice, then MRI may be used. b.CNS only disease must be measurable by MRI, CT, or by cytology and flow cytometry with EBV detected in CSF. Contrast-enhanced CT scans may be substituted in patients in whom MRI is medically contraindicated (e.g., cardiac pacemaker) or unavailable. For participants with EBV+1L PTLD where standard first line therapy (rituximab and/or chemotherapy) is inappropriate, including CD20negative disease
3. 9. Biopsy-proven EBV+ PTLD for whom standard first line therapy is inappropriate
4. 10. Subjects must have systemic disease measurable per Lugano Classification criteria, by PET-diagnostic CT as evidenced by 18Fdeoxyglucose avidity.
5. 11. For participants with Sarcoma, including LMS, or smooth muscle tumors. EBV+ sarcoma or smooth muscle tumor with rapidly progressive disease defined as progressive disease per RECIST 1.1 criteria as documented radiographically within a 6-month interval prior to enrollment.
6. 12. Biopsy-proven EBV+ sarcoma meeting one of the following criteria: a.Pathologically confirmed EBV+ Leiomyosarcoma b.EBV+ Sarcoma or smooth muscle tumor
7. 13. Measurable disease using CT, and/or MRI following RECIST 1.1 criteria
8. 2. Adequate organ function, unless organ dysfunction is considered to be due to the underlying EBV-associated disease
9. 3. Males and females of any age
10. 4. Provided written informed consent and assent, if required by law for pediatric subjects in accordance with the requirements
11. 5. For participants with PID LPD - Relapsed and/or refractory (R/R) or newly diagnosed PID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator. LPD confirmed by at least 1 of the following: a. Biopsy-proven EBV+ LPD b. Positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF. Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: a.Radiographic disease progression per Lugano Classification during or after treatment b.Failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
12. 6. Subjects may have systemic disease only, systemic and CNS disease or CNS disease only, meeting one of the following criteria: a. Systemic disease measurable per Lugano Classification criteria, by PET-CT as evidenced by 18F-deoxyglucose avidity, except when contraindicated or mandated by local practice, then MRI may be used. b.CNS only disease measurable by MRI, CT, or by cytology and flow cytometry with EBV detected in CSF
13. 7. For participants with CNS PTLD. R/R or newly diagnosed CNS PTLD for whom the standard first line therapy is inappropriate, as determined by the investigator, confirmed by at least 1 of the following: a.Biopsy-proven EBV+ CNS PTLD, b.Positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF. Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: a.Radiographic disease progression per Lugano Classification during or after treatment b.Failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy

Exclusion criteria 12

1. Currently active Burkitt, T cell, natural killer (NK)/T-cell lymphoma/LPD, Hodgkin, plasmablastic, transformed lymphoma, active hemophagocytic lymphohistiocytosis, or other malignancies requiring systemic therapy
2. Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment, or known history of human immunodeficiency virus (HIV) infection
3. Suspected or confirmed grade ≥ 2 acute (GvHD) per the CIBMTR consensus grading system or moderate/severe chronic GvHD per NIH consensus criteria at the time of the enrollment
4. Need for vasopressor or ventilatory support at the time of enrollment.
5. Prior therapy (in order of increasing washout period) prior to enrollment, as follows: a. Within 4 weeks or 5 half-lives (whichever is shorter): i. Any investigational product (co-enrollment in a non-interventional study or a study for sample collection only is permitted) ii. Any chemotherapy (systemic or intrathecal), targeted small molecule therapy, or antibody/biologic therapy. Note: prior anti-CD20 antibody use is permitted within the washout period if a subsequent disease response assessment indicates disease progression. B. Within 8 weeks: i. Prior tabelecleucel (>8 weeks prior to enrollment) is permitted (in consultation with the Medical Monitor) if response was obtained or if usual protocol-directed therapeutic options were not exhausted (e.g., restriction switch options) ii. Cellular therapies: chimeric antigen receptor (CAR) therapies directed at T cells or T cell subsets, donor lymphocyte infusion, other CTLs, or virus-specific T cells iii. Therapies which could impact tabelecleucel function: Anti-thymocyte globulin, alemtuzumab C. Any prior treatment with EBV-CTLs with the exception of tabelecleucel as above
6. Female who is breastfeeding or pregnant
7. Any of the following while undergoing treatment with tabelecleucel and for 90 days after the last dose (details are specified in the body of the protocol): For females of childbearing potential: 1) unwilling to use a highly effective method of contraception (i.e., one that can achieve a failure rate of less than 1% per year when used consistently and correctly) or 2) unwilling to refrain from donating eggs For males: 1) unwilling to use a condom during sexual intercourse or 2) unwilling to refrain from donating sperm or 3) has a female partner of childbearing potential who is unwilling to use a highly effective method of contraception (refer to protocol Section 5.6.4)
8. Inability or unwillingness to comply with all study procedures
9. Ongoing need for daily steroids of >0.5 mg/kg prednisone or glucocorticoid equivalent ongoing methotrexate, or extracorporeal photopheresis. For subjects with CNS disease, protocol specified dexamethasone is permitted
10. Any conditions that may put the study outcomes at undue risk: a. Life expectancy < 60 days b. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk
11. Exclusion Criteria for Participants with PID LPD or AID LPD (cohort closed in Amendment 3 after completion of stage 1) only History of prior allogeneic HCT or SOT
12. Exclusion Criteria for participants with EBV+ 1L PTLD, where standard first-line therapy (rituximab and/or chemotherapy) is inappropriate, including CD20-negative disease Prior systemic therapy for PTLD

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The ORR obtained following administration of tabelecleucel with up to different human leukocyte antigen (HLA) restrictions

Secondary endpoints 5

1. Overall survival (OS)
2. Duration of response (DOR)
3. Progression-free survival (PFS)
4. For EBV-associated lymphoproliferative disease in the setting of primary imunodeficiency (EBV+ PID LPD) cohort: Number of participants who reach definitive therapy (i.e., allogeneic HCT) for the underlying disease. Time to definitive therapy.
5. For EBV+ sarcoma cohort, including leiomyosarcoma (LMS), or smooth muscle tumors: Clinical benefit rate. ORR by immune response evaluation criteria in solid tumors (iRECIST) criteria [Seymour 2017]

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pierre Fabre Medicament

Sponsor organisation

Pierre Fabre Medicament

Address

Les Cauquillous

City

Lavaur

Postcode

81500

Country

France

Scientific contact point

Organisation

Pierre Fabre Medicament

Contact name

Pierre Fabre Medicament

Public contact point

Organisation

Pierre Fabre Medicament

Contact name

Pierre Fabre Medicament

Third parties 5

Locations

5 EU/EEA countries · 13 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 77 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications